CN101065346A - Method for the preparation of sevoflurane - Google Patents

Method for the preparation of sevoflurane Download PDF

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CN101065346A
CN101065346A CNA2005800392651A CN200580039265A CN101065346A CN 101065346 A CN101065346 A CN 101065346A CN A2005800392651 A CNA2005800392651 A CN A2005800392651A CN 200580039265 A CN200580039265 A CN 200580039265A CN 101065346 A CN101065346 A CN 101065346A
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sevoflurane
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CN101065346B (en
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R·C·特雷尔
J·A·乐文森
C·W·杨
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Minrad Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/04—Saturated ethers
    • C07C43/12—Saturated ethers containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/04—Saturated ethers
    • C07C43/13—Saturated ethers containing hydroxy or O-metal groups

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Abstract

A method for the preparation of (CF<SUB>3</SUB>)<SUB>2</SUB>CHOCH<SUB>2</SUB>F (Sevoflurane) is presented, which comprises providing a mixture of (CF<SUB>3</SUB>)<SUB>2</SUB>CHOCH<SUB>2</SUB>Cl, potassium fluoride, water, and a phase transfer catalyst and reacting the mixture to form (CF<SUB>3</SUB>)<SUB>2</SUB>CHOCH<SUB>2</SUB>F.

Description

The method for preparing Sevoflurane
Contrast with related application
The denomination of invention that the applicant requires on November 17th, 2004 to submit to is the right of priority of the U.S. Provisional Patent Application 60/628,707 of " method for preparing Sevoflurane ", and the content of this patent application is inserted this paper by reference.
Invention field
The present invention relates to suck the narcotic field.Specifically, the present invention relates to preparation (CF 3) 2CHOCH 2The method of F (that is, sevoflurane (Sevoflurane)).
Background of invention
The present invention relates to fluoridize (CF 3) 2CHOCH 2Cl is to produce (CF 3) 2CHOCH 2The method of F (sevoflurane), (CF 3) 2CHOCH 2F is a kind of of great value inhalation anesthetic, especially can be used for outpatient operation and associated with conscious sedation.
A lot of methods can be used for synthetic fluorinated compound such as sevoflurane.Wherein the most useful a kind of method is to prepare earlier chlorinated compound (CF 3) 2CHOCH 2Cl (heptachlor alkane (sevochlorane)) (its preparation method is described in United States Patent (USP) 3,476,860 and 3,683,092) carries out halogenation by halogen exchange reaction then.See formula (1).
(1)(CF 3) 2CHOCH 3→(CF 3) 2CHOCH 2Cl→(CF 3) 2CHOCH 2F
Yet, found in halogen exchange reaction, to use potassium fluoride to be subjected to the low restriction of fluorinated product productive rate, productive rate is low to be to be caused by the side reaction that produces elimination and hydrolysate and some other factor.Specifically, find when having a certain amount of water, can to form a large amount of hydrolysates, the impurity that generation must be removed, and seriously reduce the productive rate of required fluorinated product.
For example, reported with a lot of methods and made the reaction of chloralkane and potassium fluoride.Landini etc. (Synthesis, 1428 (1974)) have reported that alkyl halide and potassium fluoride react the generation fluoroalkane in the presence of phase transfer catalyst.This reaction is not to carry out with anhydrous potassium fluoride, but carries out in aqueous medium.In this medium, thereby taking place, significant hydrolysis produced by-product alcohols.
Dermeik etc. (J.Org.Chem., the 50th volume, 879-882 page or leaf, 1985) have described the impact of the reaction that water carries out potassium fluoride and alkyl halide in the presence of phase transfer catalyst.The document points out, with respect to the lower water-content of fluorizating agent corresponding to producing low hydrolysate.These data show that for the amount that makes hydrolysate in the final product mixture is lower than 4mol%, the mol ratio of Potassium monofluoride and water must be greater than 15.
Describe according to (Tetrahedron Letters, the 27th volume, No.13, pp.1499-1500 (1985)) such as Escoula, for the fluoro-chlorine permutoid reaction that adopts phase-transfer catalyst, methane amide is better than water as reaction medium.Under this condition, obtained high yield.Therefore, if productive rate is very important, fluorination reaction is generally carried out under such condition, namely solvent be or at least major part be nonaqueous solvents.The as noted above United States Patent (USP) 3,683,092 of example has been described with thiophane (thiophane-1,1-dioxide) and has been fluoridized (CF as solvent with potassium fluoride 3) 2CHOCH 2CI; See formula (2).
Figure A20058003926500051
Above-mentioned document relates in general to fluoridizing of chloroparaffin.It will be understood by those skilled in the art that when fluoridizing cloroecther, issue unboiled water in the existence of water and separate and make this problem of ether bond rupture more serious.Particularly, known 2-chloro-ether in the presence of water than alkane facile hydrolysis more.In relating to other document that cloroecther fluoridizes, strictly the existence of water is namely eliminated or avoid to control or the existence of carefully avoiding water in the cloroecther fluorination process fully to such degree.
M.Hudlicky, " organofluorine compound chemistry " ( Chemistry of Organic Fluorine Compounds), revised edition for the second time, Ellis Horwood Ltd. (1992) has summarized and has used Potassium monofluoride as the chlorine in the reagent substituted organic compound.Document instruction, successfully Potassium monofluoride is used for the very poor halogen atom of substitution reaction, the success of this method has been to adopt suitable solvent such as ethanamide, oil of mirbane, dimethyl sulfoxide (DMSO), dimethyl sulfone, tetramethylene sulfone, especially ethylene glycol and glycol ether.The document is also instructed, and in order to obtain maximum yield, must use pure, the absolute chemicals of doing (that is, anhydrous).Except other chemicals, above-mentioned document specifies in conjunction with halogen-containing ether.
United States Patent (USP) 4,874,901 have described with anhydrous potassium fluoride and have not added solvent and fluoridized (CF 3) 2CHOCH 2Cl.This is reflected under the high temperature (185 ℃-283 ℃) and carries out.Reaction pressure up to 1100psig is disclosed.Synthesized sevoflurane with this method, conversion ratio is 60%, and productive rate is 75%.
United States Patent (USP) 6,100,434 have also described water to (CF 3) 2CHOCH 2The impact that Cl fluoridizes.Although it discloses the existence of tolerable water, a large amount of water has increased the possibility of hydrolysis.And the document discloses because (CF 3) 2CHOCH 2Cl is relative unmixing in water, and relatively large water may hinder fluorination reaction.The document is also instructed, if make water in this reaction, then water is as cosolvent (that is, not making water when not having another kind of vehicle substance).
Yet water is a kind of convenient solvent that uses.And water usually is present in the fluorination reaction commonly used reagent and fluorization agent, in this case, do not adopt extra purification step to be difficult to avoid have in the fluorination reaction water to exist.Yet water is difficult to remove from reaction product unlike the impurity of a lot of other types.The chlorine ether that therefore, need to carry out in aqueous medium in this area is such as (CF 3) 2CHOCH 2The high yield of Cl, the fluorination reaction of low in hydrolysis.
Summary of the invention
It is shocking, find (CF 3) 2CHOCH 2Cl can react with potassium fluoride in the presence of water and phase transfer catalyst (preferably not having organic cosolvent), obtains good (CF 3) 2CHOCH 2Conversion ratio and the productive rate of F (sevoflurane), and be hydrolyzed minimum.For example, in the fluoridation of carrying out according to the inventive method, hydrolysis usually only takes place less than 5wt% in the heptachlor alkane that adds in the reaction vessel, and based on the amount of the heptachlor alkane that consumes in the reaction, the molecule productive rate is usually greater than 50%.
Therefore, the invention provides a kind of (CF for preparing 3) 2CHOCH 2The new method of F.This method is included under water and the phase transfer catalyst existence and makes (CF 3) 2CHOCH 2Cl and potassium fluoride reaction.Can under moderate temperature and pressure, carry out this reaction, (CF 3) 2CHOCH 2Cl is to (CF 3) 2The hydrolysis of CHOH is few.
Detailed Description Of The Invention
In the inventive method, starting compound (CF 3) 2CHOCH 2Cl reacts with potassium fluoride in the presence of water and phase transfer catalyst.Described starting compound (CF 3) 2CHOCH 2Cl is known compound, can be by a lot of route of synthesis preparations.For example, it is synthetic to be described in United States Patent (USP) 3,476, in 860 and 3,683,092.Although (CF 3) 2CHOCH 2Cl is incorporated in the fluorination reaction with the form of purifying usually, but purifying is for realizing that benefit of the present invention is generally optional.Therefore, if need, can be at raw materials (CF 3) 2CHOCH 2Carry out described fluorination reaction in the same container of Cl or the space, get final product " cooking-pot type is synthetic " described sevoflurane.
Available a lot of mode is carried out fluoridation.Usually, carry out fluorination reaction with intermittent mode: mix (CF 3) 2CHOCH 2Cl, potassium fluoride, water and phase transfer catalyst heat this reactant mixture a period of time then to form compound of reaction, stir simultaneously or carry out the stirring of another kind of form.The order that these four kinds of components add is inessential.Can semi-batch mode carry out this reaction, add continuously in heating with when stirring reaction mixture this moment or remove one or more reactants or product.For example, if add raw material in semi-batch process, then the reactant of Jia Ruing (or " restricted " reactant) can be heptachlor alkane (joining in water/Potassium monofluoride/phase-transfer catalysis agent solution) or water/potassium fluoride solution (joining in heptachlor alkane/catalyst mixture).Also can use the operate continuously mode, add continuously reactant and catalyzer this moment, heat and stir this reaction mixture and remove sevoflurane product continuously to form reaction mixture.
Though preferably in 60 ℃ of-100 ℃ of temperature ranges, carry out this reaction, also can adopt the temperature outside this scope, higher temperature is usually corresponding to higher fluorination rates.Reaction pressure can be low to moderate 0psig, preferably in the 0-105psig scope.Reaction pressure is usually relevant with mode of operation (being closed vs. open container) with reaction temperature.Generally, higher pressure can be observed the gaseous reaction products accumulation corresponding to higher temperature and corresponding to such reaction pattern.
Usually, the reaction times how to carry out yet the reaction times can be depending on reaction, and the reaction times can be outside described scope in 3-16 hour scope.For example, the reaction rate of reaction continuous or semi-batch can be subjected to reactant (such as potassium fluoride or (CF in dynamics 3) 2CHOCH 2Cl) the restriction of feeding in raw material or removing.And the reaction times is also depended on temperature, and higher temperature is tended to corresponding higher fluorination rates and short reaction times.
Various forms of suitable Potassium monofluorides be can commercially availablely buy, sheet, granular (coarse grain or particulate) or the aqueous solution comprised.It needs not be anhydrous, drying or segmentation.Used Potassium monofluoride also can be that salt hydrate is (as dihydrate KF-2H 2O and tetrahydrate KF-4H 2O) form, its form are granular, sheet or other form.In addition, the part or all of potassium fluoride of adding can be that acid salt (is KHF 2) form, it also can have the form of sheet, the granular or aqueous solution; With respect to independent use potassium fluoride, adopt acid salt to provide the available fluorine ion of a part usually can increase the productive rate of fluorinated product.Every mole of (CF 3) 2CHOCH 2The molal quantity of the employed potassium fluoride of Cl is usually above 0.1: 1, preferably 1: 1-2: in 1 scope; Yet, the invention is not restricted to these and preferably measure.
By fluoride salt used in the reaction and the gross weight of water, the weight of the fluoride salt of mixing (that is, potassium fluoride and Fremys salt) should be greater than 25wt%, preferably in the 35wt%-50wt% scope.Yet, the invention is not restricted to these and preferably measure, because also can produce a large amount of sevofluranes in the relative weight that is higher or lower than this scope; The actual weight of using during the variation of conversion ratio, productive rate and hydrolysis is reacted affects.
If need, except (CF 3) 2CHOCH 2Also can in reaction, use one or more aqueous acid to promote (CF outside Cl, phase transfer catalyst, KF and the water 3) 2CHOCH 2The generation of F.Suitable acid comprises hydrochloric acid or hydrofluoric acid; Also can use other organic or inorganic acid.By (the CF that adds in the reaction 3) 2CHOCH 2The weighing scale of Cl, the amount of acid is preferably in the 1-3wt% scope; Yet, the invention is not restricted to these and preferably measure, because littler or relatively large acid generally also can provide low in hydrolysis benefit of the present invention.
By (the CF that adds in the reaction 3) 2CHOCH 2The weighing scale of Cl, the amount of institute's water are generally greater than 1wt%, preferably in the 10-50wt% scope.Yet, the invention is not restricted to these preferably measures, because also available more or less water suitably generates fluorinated product, though water base that most preferably joins in the reaction mixture does not contain (promptly, content is less than the 1wt% of the water that adds) other solvent or impurity, but these materials can preferably be not more than the amount of 50wt% to be existed, more preferably no more than 20wt%.Example comprises dissolved salt, water-soluble organic compounds, organic solvent etc., and the form that they can unavoidable impurities exists or as functional component.
By the molar weight of the heptachlor alkane that reacts, the molecule productive rate of Sevoflurane is preferably greater than 60% generally greater than 50%.By the weighing scale that adds the heptachlor alkane in the reaction, hydrolysate (((CF 3) 2CHOH) generally be lower than 15wt%, preferably be lower than 10wt%.
Can use various phase-transfer catalysts.Commercially available phase-transfer catalyst comprises that quaternary ammonium salt is (as Aliquat175, Aliquat 336 and benzyltriethylammonium chloride), season   salt (as chlorinated butyl triphenyl  and Diethylaminoethyl triphenyl ), polyoxyethylene glycol (as polyoxyethylene glycol dibutyl ether and polyoxyethylene glycol dimethyl ether), crown ether (as 18-hat-6 and dibenzo-18-hat-6), ionic liquid (ionic liquids) (as guanidinesalt and imidazolium salts), chipal compounds (as chlorination anthrol methyl cinchovatin  salt (anthracenylmethyl cinchonidiniumchloride)) and high temperature reagent (as Aliquat HTA-I).Yet, the invention is not restricted to these particular compound, also can adopt other phase transfer catalyst of above type and their combination.By (the CF that adds in the reaction 3) 2CHOCH 2The weighing scale of Cl, the consumption of used phase transfer catalyst are generally greater than 0.25wt%, usually in the 1-5wt% scope; Preferably measure yet the invention is not restricted to these, because can suitably produce fluorinated product with the phase transfer catalyst of greater or lesser ratio and significant hydrolysis does not take place.
Can be by washing reactant mixture with water or carrying out azeotropic distillation and come reaction product isolated (CF by adding or not adding water 3) 2CHOCH 2F (sevoflurane).Can be further purified this crude reaction product by fractionation.Available other purifying known in the art and separation method reclaim or are further purified described sevoflurane product, and these methods comprise the method for utilizing gas-chromatography, extraction, absorption and elution.
Following examples are used for explaining better the enforcement of the preferred embodiment for the present invention.These embodiment only are used to the purpose explained, and the unrestricted scope of the invention.In these embodiments, adopt following commercially available phase-transfer catalyst (Kankakee IL60901), is expressed as follows for Cognis Corporation, 2505 South Kensington Road:
Aliquat 175 methyl chloride TBuAs
Aliquat 100 Tetrabutylammonium bromides
Aliquat 336 bromination tricaprylmethylammoniums
The patented chlorination alkylammonium of Aliquat HTA-1 mixture
Gas chromatographic analysis is carried out with the SE-30 chromatographic column, program be 55 ℃ 4 minutes, be elevated to 130 ℃ with 4 ℃/minute speed then.All wt percentage number average is based on the gross weight of the product mixtures that reclaims among the embodiment.The weight of term " product mixtures of recovery " does not comprise the weight of hydrochloric acid and formaldehyde reaction product, and they generally are removed in reacted processing and/or purification step.Conversion ratio is calculated as reaction (CF 3) 2CHOCH 2The Cl molal quantity is divided by (the CF that joins in the reaction vessel 3) 2CHOCH 2The Cl molal quantity, (the CF of calculation of yield for forming 3) 2CHOCH 2The F molal quantity is divided by (the CF of reaction 3) 2CHOCH 2The Cl molal quantity.
Embodiment 1: chlorine ether raw material and water reaction
With 15g (0.069mol) (CF 3) 2CHOCH 2The mixture of Cl and 15g water in the autoclave of 100cc 90 ℃ added thermal agitation 1.5 hours.With Dean Stark trap by azeotropic distillation to reclaim product.The heavy 13.4g of the product that reclaims uses gas chromatographic analysis.Product is 78.6% (CF 3) 2CHOCH 2Cl and 21.2% (CF 3) 2CHOH shows significant hydrolysis takes place.Transformation efficiency is 30%.
Embodiment 2: chlorine ether is fluoridized under the situation that does not add water again
With 43.2g (0.2mol) (CF 3) 2CHOCH 2The slurries of Cl, 11.6g (0.2mol) potassium fluoride, 1.56g (0.02mol) Fremys salt and 1g Aliquat HTA-I in the 100cc autoclave 100 ℃ added thermal agitation 3 hours; Do not add extra water, water is only from HTA-I solution (less than 0.6g).With Dean Stark trap by azeotropic distillation with product and moisture from.The heavy 30.1g of the product that reclaims uses gas chromatographic analysis.Product is 75% (CF 3) 2CHOCH 2F, 19% (CF 3) 2CHOCH 2Cl and 3% (CF 3) 2CHOH.Transformation efficiency is 87%, and productive rate is 65%.Conversion ratio is than much lower in the situation that adds again extra water.This embodiment proves, uses less than 10wt% (by (CF that joins in the reaction vessel in the time of the catalyst that uses appropriate amount and potassium fluoride salt 3) 2CHOCH 2When the water Cl weighing scale) carries out fluorination reaction, obtained lower productive rate.
Embodiment 3: deposit fluoridizing of chlorine ether when not using phase-transfer catalyst
With (CF 3) 2CHOCH 2Cl 43.2g (0.2mol), 40% potassium fluoride aqueous solution 29g (0.2mol KF) and the mixture of Fremys salt 1.56g (0.02mol) that is dissolved in 2.34g water in the autoclave of 100cc 90 ℃ added thermal agitation 12 hours; Do not use phase transfer catalyst.With Dean Stark trap by azeotropic distillation to reclaim product.The heavy 38.3g of the product that reclaims uses gas chromatographic analysis.Product is 34.9% (CF 3) 2CHOCH 2F, 60.1% (CF 3) 2CHOCH 2Cl and 4.7% (CF 3) 2CHOH.Transformation efficiency is 47%, and productive rate is 71.7%.Observe transformation efficiency and productive rate is low, show that phase-transfer catalyst higher conversion and productive rate of (fluoridation) when having water is essential.
Embodiment 4: chlorine ether fluoridized when water was excessive greatly
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mol), potassium fluoride 5.8g (0.1mol), Fremys salt 0.78g (0.01mol), 59.98g water and 0.5g Aliquat HTA-I in the 100cc autoclave 90 ℃ added thermal agitation 12 hours.With Dean Stark trap by azeotropic distillation to reclaim product.The heavy 17.0g of the product that reclaims uses gas chromatographic analysis.Product is 22.8% (CF 3) 2CHOCH 2F, 0.75% (CF 3) 2CHOCH 2Cl and 74.4% (CF 3) 2CHOH.Transformation efficiency is 99.4%, and productive rate is 19.5%.This embodiment proves, exists greater than about 50wt% (by (CF that adds in the reaction vessel in the time of the catalyst that uses appropriate amount and potassium fluoride salt 3) 2CHOCH 2During the weighing scale of Cl) water, the productive rate of observing sevoflurane is low, and simultaneously hydrolysis significantly.
Embodiment 5: when having excessive water, with KF/KHF 2Concentration dependent fluoridizing
Carried out when there is excessive water in series of experiments research potassium fluoride salt concentration to the impact of fluorination reaction.
1. with (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mol), potassium fluoride 5.8g (0.1mol), Fremys salt 0.78g (0.01mol), 31.1g water and 0.5g Aliquat HTA-I 90 added thermal agitation 3 hours in the 100cc autoclave.Reclaim product with Dean Stark trap by azeotropic distillation.The heavy 19.4g of the product that reclaims uses gas chromatographic analysis.Product is 30.98% (CF 3) 2CHOCH 2F, 41.83% (CF 3) 2CHOCH 2Cl and 26.38% (CF 3) 2CHOH.Transformation efficiency is 62%, and productive rate is 48%.
2. with (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mol), potassium fluoride 7.25g (0.125mol), Fremys salt 0.975g (0.0125mol), 31.1g water and 0.5g Aliquat HTA-I 90 added thermal agitation 3 hours in the 100cc autoclave.Reclaim product with Dean Stark trap by azeotropic distillation.The heavy 19.1g of the product that reclaims uses gas chromatographic analysis.Product is 38.39% (CF 3) 2CHOCH 2F, 46.62% (CF 3) 2CHOCH 2Cl and 14.49% (CF 3) 2CHOH.Transformation efficiency is 59%, and productive rate is 63%.
3. with (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mol), potassium fluoride 8.7g (0.15mol), Fremys salt 1.17g (0.015mol), 31.1g water and 0.5g Aliquat HTA-I 90 added thermal agitation 3 hours in the 100cc autoclave.Reclaim product with Dean Stark trap by azeotropic distillation.The heavy 19.2g of the product that reclaims uses gas chromatographic analysis.Product is 48.3% (CF 3) 2CHOCH 2F, 43.2% (CF 3) 2CHOCH 2Cl and 8.4% (CF 3) 2CHOH.Transformation efficiency is 61.6%, and productive rate is 75%.
4. with (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mol), potassium fluoride 10.15g (0.175mol), Fremys salt 1.365g (0.0175mol), 31.1g water and 0.5g Aliquat HTA-I 90 added thermal agitation 3 hours in the 100cc autoclave.Reclaim product with Dean Stark trap by azeotropic distillation.The heavy 19.4g of the product that reclaims uses gas chromatographic analysis.Product is 54.1% (CF 3) 2CHOCH 2F, 40.3% (CF 3) 2CHOCH 2Cl and 5.5% (CF 3) 2CHOH.Transformation efficiency is 64%, and productive rate is 82%.
5. with (CF 3) 2CHOCH 2The mixture of CI 21.6g (0.1mol), potassium fluoride 11.6g (0.2mol), Fremys salt 1.56g (0.02mol), 31.1g water and 0.5g Aliquat HTA-I 90 added thermal agitation 3 hours in the 100cc autoclave.Reclaim product with Dean Stark trap by azeotropic distillation.The heavy 19.4g of the product that reclaims uses gas chromatographic analysis.Product is 66.3% (CF 3) 2CHOCH 2F, 30.7% (CF 3) 2CHOCH 2Cl and 2.87% (CF 3) 2CHOH.Transformation efficiency is 72.5%, and productive rate is 89%.
These data show that the concentration of aqueous salt is to determine chlorine ether to the conversion ratio of sevoflurane and with (CF 3) 2The minimized important parameter of the generation of CHOH accessory substance.Produce than low-yield and more hydrolysis than low salt concn, higher concentration produces higher yields and less hydrolysis.
Embodiment 6
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 8.7g (0.15mole), 10g water and 1g Aliquat HTA-I 60 added thermal agitation 17 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 18.7g of the product that reclaims uses gas chromatographic analysis.Product is 71.4% (CF 3) 2CHOCH 2F and 26% (CF 3) 2CHOCH 2Cl, and a series of a small amount of unidentified accessory substance.Transformation efficiency is 77.5%, and productive rate is 86%.
Embodiment 7
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 8.7g (0.15mole), 10g water and 1g Aliquat HTA-I 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 17.4g of the product that reclaims uses gas chromatographic analysis.Product is 89% (CF 3) 2CHOCH 2F and 7% (CF 3) 2CHOCH 2CI.0.6% (CF is arranged 3) 2CHOH.Transformation efficiency is 94%, and productive rate is 82%.
Embodiment 8
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 8.7g (0.15mole), 10g water and 1g Aliquat HTA-I 100 added thermal agitation 4 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 17.7g of the product that reclaims uses gas chromatographic analysis.Product is 86.8% (CF 3) 2CHOCH 2F and 9.9% (CF 3) 2CHOCH 2CI.0.03% (CF is only arranged 3) 2CHOH.Transformation efficiency is 92%, and productive rate is 84%.
Embodiment 9
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 8.7g (0.15mole), 20g water and 1g Aliquat HTA-I 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 18.9g of the product that reclaims uses gas chromatographic analysis.Product is 86% (CF 3) 2CHOCH 2F and 10% (CF 3) 2CHOCH 2Cl.0.9% (CF is arranged 3) 2CHOH.Transformation efficiency is 91%, and productive rate is 89%.
Embodiment 10
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 11.6g (0.2mole), 20g water and 1g Aliquat HTA-I 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 18g of the product that reclaims uses gas chromatographic analysis.Product is 88.7% (CF 3) 2CHOCH 2F and 6.17% (CF 3) 2CHOCH 2Cl.0.2% (CF is only arranged 3) 2CHOH.Transformation efficiency is 95%, and productive rate is 84%.
Embodiment 11
With (CF 3) 2CHOCH 2The mixture of Cl 43.2g (0.2mole), potassium fluoride 12.76g (0.22mole), 10g water and 1g Aliquat HTA-I 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 38.1g of the product that reclaims uses gas chromatographic analysis.Product is 68.9% (CF 3) 2CHOCH 2F and 29% (CF 3) 2CHOCH 2Cl.Transformation efficiency is 74%, and productive rate is 88%.
Embodiment 12
With (CF 3) 2CHOCH 2The mixture of Cl 43.2g (0.2mole), potassium fluoride 12.76g (0.22mole), 10g water and 2g Aliquat HTA-I 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 37g of the product that reclaims uses gas chromatographic analysis.Product is 77% (CF 3) 2CHOCH 2F and 20% (CF 3) 2CHOCH 2Cl.0.18% (CF is arranged 3) 2CHOH.Transformation efficiency is 83%, and productive rate is 86%.
Embodiment 13
With (CF 3) 2CHOCH 2100 ℃ of heating of the 1.0N HCl (0.01mole) of Cl 43.2g (0.2mole), potassium fluoride 12.76g (0.22mole), 10cc and the mixture of 1g Aliquat HTA-I 3 hours.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 38.7g of the product that reclaims uses gas chromatographic analysis.Product is 80% (CF 3) 2CHOCH 2F and 18.5% (CF 3) 2CHOCH 2Cl.1.05% (CF is arranged 3) 2CHOH.Transformation efficiency is 83%, and productive rate is 93%.
Embodiment 14
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 6.38g (0.11mole), 30g water and 1g Aliquat HTA-I 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 16.1g of the product that reclaims uses gas chromatographic analysis.Product is 75% (CF 3) 2CHOCH 2F and 14% (CF 3) 2CHOCH 2Cl.8.7% (CF is arranged 3) 2CHOH.Transformation efficiency is 90%, and productive rate is 67%.
Embodiment 15
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 6.38g (0.11mole), 30g water and 0.5g Aliquat HTA-I 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 14.8g of the product that reclaims uses gas chromatographic analysis.Product is 70% (CF 3) 2CHOCH 2F and 12% (CF 3) 2CHOCH 2Cl.11.5% (CF is arranged 3) 2CHOH.Transformation efficiency is 92%, and productive rate is 57%.
Embodiment 16
With (CF 3) 2CHOCH 2The mixture of Cl 43.2g (0.2mole), potassium fluoride 11.6g (0.2mole), 10g water and 1g Aliquat HTA-I 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 38.4g of the product that reclaims uses gas chromatographic analysis.Product is 66% (CF 3) 2CHOCH 2F and 32% (CF 3) 2CHOCH 2Cl.Transformation efficiency is 72%, and productive rate is 89%.
Embodiment 17
With (CF 3) 2CHOCH 2The mixture of Cl 43.2g (0.2mole), potassium fluoride 11.6g (0.2mole), 10g water and 1g Aliquat HTA-I 100 added thermal agitation 1 hour in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 40.3g of the product that reclaims uses gas chromatographic analysis.Product is 55% (CF 3) 2CHOCH 2F and 43% (CF 3) 2CHOCH 2Cl.Transformation efficiency is 60%, and productive rate is 93%.
Embodiment 18
With (CF 3) 2CHOCH 2Cl 43.2g (0.2mole), potassium fluoride 11.6g (0.2mole), 1.56gKHF 2(0.02mole), the mixture of 10g water and 1g dichloride benzyl triethylamine 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 37.7g of the product that reclaims uses gas chromatographic analysis.Product is 85.5% (CF 3) 2CHOCH 2F and 9.5% (CF 3) 2CHOCH 2Cl.4% (CF is arranged 3) 2CHOH.Transformation efficiency is 92%, and productive rate is 88%.
Embodiment 19
With (CF 3) 2CHOCH 2Cl 43.2g (0.2mole), potassium fluoride 11.6g (0.2mole), 1.56gKHF 2(0.02mole), the mixture of 10g water and 1g Aliquat HTA-I 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 37.6g of the product that reclaims uses gas chromatographic analysis.Product is 83% (CF 3) 2CHOCH 2F and 15% (CF 3) 2CHOCH 2Cl.Transformation efficiency is 87%, and productive rate is 90%.
Embodiment 20
With (CF 3) 2CHOCH 2Cl 43.2g (0.2mole), potassium fluoride 11.6g (0.2mole), 1.56gKHF 2(0.02mole), the mixture of 20g water and 1g Aliquat HTA-I 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 39.2g of the product that reclaims uses gas chromatographic analysis.Product is 75.6% (CF 3) 2CHOCH 2F and 23.3% (CF 3) 2CHOCH 2Cl.Transformation efficiency is 79%, and productive rate is 94%.
Embodiment 21
With (CF 3) 2CHOCH 2Cl 43.2g (0.2mole), potassium fluoride 11.6g (0.2mole), 1.56gKHF 2(0.02mole), the mixture of 10g water and 1g Aliquat HTA-I 100 added thermal agitation 5 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 38.6g of the product that reclaims uses gas chromatographic analysis.Product is 80% (CF 3) 2CHOCH 2F and 16% (CF 3) 2CHOCH 2Cl.2.5% (CF is arranged 3) 2CHOH, conversion ratio are 86%, and productive rate is 90%.
Embodiment 22
With (CF 3) 2CHOCH 2Cl 43.2g (0.2mole), potassium fluoride 11.6g (0.2mole), 1.56gKHF 2(0.02mole), the mixture of 10g water and 1g Aliquat 175 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 38.3g of the product that reclaims uses gas chromatographic analysis.Product is 84% (CF 3) 2CHOCH 2F and 11% (CF 3) 2CHOCH 2Cl.3.8% (CF is arranged 3) 2CHOH.Transformation efficiency is 90%, and productive rate is 89%.
Embodiment 23
With (CF 3) 2CHOCH 2Cl 43.2g (0.2mole), potassium fluoride 11.6g (0.2mole), 1.56gKHF 2(0.02mole), the mixture of 5g water and 1g Aliquat HTA-I 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 37.1g of the product that reclaims uses gas chromatographic analysis.Product is 80.6% (CF 3) 2CHOCH 2F and 15.6% (CF 3) 2CHOCH 2Cl.2.6% (CF is arranged 3) 2CHOH.Transformation efficiency is 87%, and productive rate is 87%.
Embodiment 24
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 17.4g (0.3mole), 40g water and 1g Aliquat336 60 added thermal agitation 16 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 17.3g of the product that reclaims uses gas chromatographic analysis.Product is 75% (CF 3) 2CHOCH 2F and 21% (CF 3) 2CHOCH 2Cl.0.5% (CF is arranged 3) 2CHOH.Transformation efficiency is 83%, and productive rate is 78%.
Embodiment 25
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 8.7g (0.15mole), 10g water and 1g Aliquat 336 60 added thermal agitation 16 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 17g of the product that reclaims uses gas chromatographic analysis.Product is 68% (CF 3) 2CHOCH 2F and 28% (CF 3) 2CHOCH 2Cl.0.5% (CF is arranged 3) 2CHOH.Transformation efficiency is 78%, and productive rate is 74%.
Embodiment 26
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 8.7g (0.15mole), 10g water and 2g Aliquat 336 60 added thermal agitation 16 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 17.5g of the product that reclaims uses gas chromatographic analysis.Product is 74.7% (CF 3) 2CHOCH 2F and 17% (CF 3) 2CHOCH 2Cl.Transformation efficiency is 86%, and productive rate is 76%.
Embodiment 27
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 8.7g (0.15mole), 10g water and 1g Aliquat 336 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 17.6g of the product that reclaims uses gas chromatographic analysis.Product is 92.2% (CF 3) 2CHOCH 2F and 3.8% (CF 3) 2CHOCH 2Cl.Transformation efficiency is 97%, and productive rate is 84%.
Embodiment 28
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 6.38g (0.11mole), 10g water and 1g Aliquat336 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 17g of the product that reclaims uses gas chromatographic analysis.Product is 84% (CF 3) 2CHOCH 2F and 11% (CF 3) 2CHOCH 2Cl.Transformation efficiency is 91%, and productive rate is 78%.
Embodiment 29
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 8.7g (0.15mole), 10g water and 1g Aliquat 100 60 added thermal agitation 15 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 18.3g of the product that reclaims uses gas chromatographic analysis.Product is 77% (CF 3) 2CHOCH 2F and 20% (CF 3) 2CHOCH 2Cl.Transformation efficiency is 83%, and productive rate is 85%.
Embodiment 30
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 8.7g (0.15mole), 10g water and 1g Aliquat 100 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 17.7g of the product that reclaims uses gas chromatographic analysis.Product is 87% (CF 3) 2CHOCH 2F and 8% (CF 3) 2CHOCH 2Cl.2.6% (CF is arranged 3) 2CHOH.Transformation efficiency is 93%, and productive rate is 83%.
Embodiment 31
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 8.7g (0.15mole), 20g water and 1.7g Aliquat 100 60 added thermal agitation 15 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 18.2g of the product that reclaims uses gas chromatographic analysis.Product is 75% (CF 3) 2CHOCH 2F and 23% (CF 3) 2CHOCH 2Cl.0.4% (CF is arranged 3) 2CHOH.Transformation efficiency is 81%, and productive rate is 85%.
Embodiment 32
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 6.38g (0.11mole), 10g water and 1g Aliquat 336 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 18.1g of the product that reclaims uses gas chromatographic analysis.Product is 81% (CF 3) 2CHOCH 2F and 15% (CF 3) 2CHOCH 2Cl.1.5% (CF is arranged 3) 2CHOH.Transformation efficiency is 87%, and productive rate is 85%.
Embodiment 33
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 6.38g (0.11mole), 20g water and 1g Aliquat 336 100 added thermal agitation 5 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 16.8g of the product that reclaims uses gas chromatographic analysis.Product is 78% (CF 3) 2CHOCH 2F and 10% (CF 3) 2CHOCH 2Cl.9.9% (CF is arranged 3) 2CHOH.Transformation efficiency is 92%, and productive rate is 71%.
Embodiment 34
With (CF 3) 2CHOCH 2The mixture of Cl 43.2g (0.2mole), potassium fluoride 12.76g (0.22mole), 10g water and 2g Aliquat 336 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 36.2g of the product that reclaims uses gas chromatographic analysis.Product is 79% (CF 3) 2CHOCH 2F and 15% (CF 3) 2CHOCH 2Cl.2.5% (CF is arranged 3) 2CHOH.Transformation efficiency is 87%, and productive rate is 82%.
Embodiment 35
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 6.38g (0.11mole), 10g water and 1g Aliquat 336 100 added thermal agitation 6 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 18.6g of the product that reclaims uses gas chromatographic analysis.Product is 78.3% (CF 3) 2CHOCH 2F and 17% (CF 3) 2CHOCH 2Cl.1.4% (CF is arranged 3) 2CHOH.Transformation efficiency is 85%, and productive rate is 86%.
Embodiment 36
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 8.7g (0.15mole), 10g water and 1g Aliquat 336 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 16.9g of the product that reclaims uses gas chromatographic analysis.Product is 90.3% (CF 3) 2CHOCH 2F and 6.2% (CF 3) 2CHOCH 2Cl.0.23% (CF is arranged 3) 2CHOH.Transformation efficiency is 95%, and productive rate is 80%.
Embodiment 37
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 8.7g (0.15mole), 10g water and 0.5g Aliquat 336 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 17.5g of the product that reclaims uses gas chromatographic analysis.Product is 80.5% (CF 3) 2CHOCH 2F and 15% (CF 3) 2CHOCH 2Cl.0.12% (CF is arranged 3) 2CHOH.Transformation efficiency is 88%, and productive rate is 80%.
Embodiment 38
With (CF 3) 2CHOCH 2The mixture of Cl 21.6g (0.1mole), potassium fluoride 6.38g (0.11mole), 10g water and 1g Aliquat 336 120 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 16.8g of the product that reclaims uses gas chromatographic analysis.Product is 88.6% (CF 3) 2CHOCH 2F and 6.8% (CF 3) 2CHOCH 2Cl.2.1% (CF is arranged 3) 2CHOH.Transformation efficiency is 95%, and productive rate is 79%.
Embodiment 39
With (CF 3) 2CHOCH 2The mixture of Cl 43.2g (0.2mole), potassium fluoride 12.8g (0.22mole), 7.92g water and 1g etamon chloride 100 added thermal agitation 3 hours in the 100cc autoclave.Add the salt of entry, reclaim product by component distillation with Dean Stark trap with dissolution precipitation.The heavy 37g of the product that reclaims uses gas chromatographic analysis.Product is 79% (CF 3) 2CHOCH 2F and 17% (CF 3) 2CHOCH 2Cl.Transformation efficiency is 85%, and productive rate is 86%.
Embodiment 40
With 43.2g (CF 3) 2CHOCH 2The mixture of Cl (0.2mole), 20.7g two hydration potassium fluorides (0.22mole) and 1g Aliquat HTA-I 100 added thermal agitation 3 hours in the 100cc autoclave.From water, reclaim product with Dean Stark trap by azeotropic distillation.The heavy 37g of the product that reclaims uses gas chromatographic analysis.Product is 67% (CF 3) 2CHOCH 2F and 31% (CF 3) 2CHOCH 2Cl.Transformation efficiency is 73%, and productive rate is 85%.
Embodiment 41
With 43.2g (CF 3) 2CHOCH 2The mixture of Cl (0.2mole), 18.8g two hydration potassium fluorides (0.2mole) and 1gAliquat HTA-I 100 added thermal agitation 3 hours in the 100cc autoclave.From water, reclaim product with Dean Stark trap by azeotropic distillation.The heavy 38g of the product that reclaims uses gas chromatographic analysis.Product is 69% (CF 3) 2CHOCH 2F and 29% (CF 3) 2CHOCH 2Cl.Transformation efficiency is 74%, and productive rate is 88%.
Embodiment 42
With 43.2g (CF 3) 2CHOCH 2Cl (0.2mole), 18.8g two hydration potassium fluorides (0.2mole), 1.56g (0.02mole) KHF 2In the 100cc autoclave, 100 added thermal agitation 13 hours with the mixture of 1g Aliquat HTA-I.From water, reclaim product with Dean Stark trap by azeotropic distillation.The heavy 37.8g of the product that reclaims uses gas chromatographic analysis.Product is 79.4% (CF 3) 2CHOCH 2F and 17.8% (CF 3) 2CHOCH 2Cl.There is 1.6% (CF 3) 2CHOH.Transformation efficiency is 84%, and productive rate is 89%.
Embodiment 43
With 43.2g (CF 3) 2CHOCH 2The mixture of Cl (0.2mole), 20.7g two hydration potassium fluorides (0.22mole) and 1g etamon chloride 100 added thermal agitation 3 hours in the 100cc autoclave.From water, reclaim product with Dean Stark trap by azeotropic distillation.The heavy 37g of the product that reclaims uses gas chromatographic analysis.Product is 79% (CF 3) 2CHOCH 2F and 17% (CF 3) 2CHOCH 2Cl.There is 0.08% (CF 3) 2CHOH.Transformation efficiency is 85%, and productive rate is 86%.
Embodiment 44
With 43.2g (CF 3) 2CHOCH 2Cl (0.2mole), 18.8g two hydration potassium fluorides (0.2mole), 1.56g (0.02mole) KHF 2In the 100cc autoclave, 100 added thermal agitation 6 hours with the mixture of 1g Aliquat HTA-I.By washing the recovery product with water.The heavy 35.8g of the product that reclaims uses gas chromatographic analysis.Product is 89% (CF 3) 2CHOCH 2F and 8% (CF 3) 2CHOCH 2Cl.There is 2.2% (CF 3) 2CHOH.Transformation efficiency is 93%, and productive rate is 86%.
Embodiment 45
With 43.2g (CF 3) 2CHOCH 2The mixture of Cl (0.2mole), 18.8g two hydration potassium fluorides (0.2mole) and 1g Aliquat HTA-I 100 added thermal agitation 6 hours in the 100cc autoclave.From water, reclaim product with Dean Stark trap by azeotropic distillation.The heavy 37.6g of the product that reclaims uses gas chromatographic analysis.Product is 73% (CF 3) 2CHOCH 2F and 20% (CF 3) 2CHOCH 2Cl.There is 4% (CF 3) 2CHOH.Transformation efficiency is 83%, and productive rate is 83%.
Embodiment 46
With 43.2g (CF 3) 2CHOCH 2The mixture of Cl (0.2mole), 20.7g two hydration potassium fluorides (0.22mole) and 1g Aliquat HTA-I 100 added thermal agitation 3 hours in the 100cc autoclave.From water, reclaim product with Dean Stark trap by azeotropic distillation.The heavy 37.3g of the product that reclaims uses gas chromatographic analysis.Product is 77% (CF 3) 2CHOCH 2F and 18% (CF 3) 2CHOCH 2Cl.There is 3% (CF 3) 2CHOH.Transformation efficiency is 84%, and productive rate is 85%.

Claims (25)

1. one kind prepares (CF 3) 2CHOCH 2The method of F (sevoflurane), described method comprise formation (CF 3) 2CHOCH 2The mixture of Cl, potassium fluoride, water and phase transfer catalyst, thus sevoflurane formed.
2. the method for claim 1 is characterized in that, adds (the CF in the reaction vessel 3) 2CHOCH 2Cl has less than 5wt% and is hydrolyzed.
3. the method for claim 1 is characterized in that, (the CF that reaction consumes 3) 2CHOCH 2Have among the Cl greater than 50 moles of % and change into sevoflurane.
4. the method for claim 1 is characterized in that, described reaction mixture is heated to 60 ℃ of-100 ℃ of temperature, and pressure is in about 0psig-105psig scope, and the time is in about 3-16 hour scope.
5. method as claimed in claim 3 is characterized in that, one or more phase-transfer catalysts are selected from quaternary ammonium salt, season   salt, polyoxyethylene glycol, crown ether, ionic liquid, chipal compounds or high temperature reagent.
6. the method for claim 1 is characterized in that, described mixture also comprises hydrochloric acid, hydrofluoric acid or other inorganic or organic acid, by (the CF that adds in the reaction vessel 3) 2CHOCH 2The Cl weighing scale, the amount of these acid is in the 1-3% scope.
7. the method for claim 1 is characterized in that, described reaction mixture also comprises Fremy (KHF 2) or the Potassium monofluoride hydrate salt.
8. a method for preparing sevoflurane comprises: mix in reaction vessel and comprise (CF 3) 2CHOCH 2The component of Cl, potassium fluoride, water and phase transfer catalyst is to form reactant mixture, wherein every mole of (CF 3) 2CHOCH 2The mole of the potassium fluoride that Cl adds is greater than 0.1: 1, by (the CF that adds in the reaction vessel 3) 2CHOCH 2The amount that Cl weighing scale, phase transfer catalyst exist is greater than 0.25%, and the amount that water exists is so that potassium fluoride weight, with respect to the gross weight of potassium fluoride and water, greater than 25%; Wherein formed sevoflurane.
9. method as claimed in claim 8, it also comprises the step that described reaction mixture is heated to 60 ℃ of-100 ℃ of temperature, reaction pressure is in about 0psing-105psig scope.
10. method as claimed in claim 8 also comprises the step of separation of sevoflurane from reaction mixture.
11. method as claimed in claim 9 also comprises the step of separation of sevoflurane from reaction mixture.
12. method as claimed in claim 8 is characterized in that, with respect to the every mole of (CF that joins in the reaction vessel 3) 2CHOCH 2Cl, the mole of potassium fluoride is 1: 1-2: in 1 molar range, by (the CF that adds in the reaction vessel 3) 2CHOCH 2Cl weighing scale, the amount of phase transfer catalyst are in the 1-5% scope, by (the CF that adds in the reaction vessel 3) 2CHOCH 2The Cl weighing scale, the amount of water is in the 10-50% scope.
13. method as claimed in claim 8 is characterized in that, described mixture also comprises hydrochloric acid, hydrofluoric acid or other inorganic or organic acid, by (the CF that adds in the reaction vessel 3) 2CHOCH 2The Cl weighing scale, the amount of these acid is in the 1-3% scope.
14. method as claimed in claim 8 is characterized in that, one or more phase-transfer catalysts are selected from quaternary ammonium salt, season   salt, polyoxyethylene glycol, crown ether, ionic liquid, chipal compounds or high temperature reagent.
15. method as claimed in claim 8 is characterized in that, described reaction mixture also comprises Fremy (KHF 2) or the Potassium monofluoride hydrate salt.
16. method as claimed in claim 8 is characterized in that, adds (the CF in the reaction vessel 3) 2CHOCH 2Cl has less than 5wt% and is hydrolyzed, and (the CF that consumes in the reaction 3) 2CHOCH 2Have among the Cl greater than 50 moles of % and change into sevoflurane.
17. a product mixtures that forms with the described method of claim 8 contains Sevoflurane, heptachlor alkane and heptachlor alkane hydrolysate.
18. product mixtures as claimed in claim 17 is characterized in that, adds (the CF in the reaction vessel 3) 2CHOCH 2Cl has less than 5wt% and is hydrolyzed.
19. product mixtures as claimed in claim 17 is characterized in that, (the CF that consumes in the reaction 3) 2CHOCH 2Have among the Cl greater than 50 moles of % and change into sevoflurane.
20. product mixtures as claimed in claim 17 is characterized in that, described reaction mixture also comprises Fremy (KHF 2) or the Potassium monofluoride hydrate salt.
21. product mixtures as claimed in claim 17 is characterized in that, described mixture also comprises hydrochloric acid, hydrofluoric acid or other inorganic or organic acid, by (the CF that adds in the reaction vessel 3) 2CHOCH 2The Cl weighing scale, the amount of these acid is in the 1-3% scope.
22. product mixtures as claimed in claim 18 is characterized in that, one or more phase-transfer catalysts are selected from quaternary ammonium salt, season   salt, polyoxyethylene glycol, crown ether, ionic liquid, chipal compounds or high temperature reagent.
23. Sevoflurane with the described method preparation of claim 10.
24. the method for claim 1 also comprises the step of separation of sevoflurane from reaction mixture.
25. Sevoflurane with the described method preparation of claim 24.
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WO2014114110A1 (en) * 2013-01-22 2014-07-31 福建博特化学品有限责任公司 Application of 8-substituted biguanide salt as synthetic catalyst of fluorine methyl hexafluoro isopropyl ether and catalytic synthetic method
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